Although the exposure of individuals to moderate sunlight has many beneficial effects, including the synthesis of vitamin D and the killing of certain pathogens, over-exposure of human skin to sunlight and, in particular, to the ultraviolet band of the spectrum, has many deleterious effects, including sunburn, phototoxicity, photoallergic reactions, photoaging, and the promotion of skin cancers. As a result of concerns about the deleterious effects of over-exposure to sunlight, much research has been directed to the development of both topical and systemic photoprotective agents and preparations for use in cosmetics and sunscreens (for reviews, see M. A. Pathak, Dermatologic Clinics 4(2):321-334 (1986); M. A. Pathak, "Topical and Systemic Photoprotection of Human Skin Against Solar Radiation," in H. W. Lim and N. A. Sotek, (eds.), Clinical Photomedicine, New York, Marcel Dekker, Inc. (1993); M. A. Pathak and T. B. Fitzpatrick, "Preventive Treatment of Sunburn, Dermatoheliosis, and Skin Cancer with Sun-Protective Agents," in Fitzpatrick, T. B., et al., (eds.), Dermatology in General Medicine, 4th Edition, New York, McGraw-Hill, (1994)).
In general, topical photoprotective preparations "sunscreens" can be categorized as chemical, physical, mixed. Topical chemical sunscreen preparations are usually translucent preparations that contain one or more ultraviolet-absorbing compounds. Topical physical sunscreen preparations are usually opaque or semi-opaque preparations that contain compounds that do not necessarily absorb ultraviolet radiation but, rather, reflect or scatter radiation UV because of their opacity and particle size (30-100 nm). Topical mixed sunscreen preparations contain a mixture of chemical and physical sunscreen agents. Topical sunscreen preparations are generally formulated as solutions (in, e.g., alcohol; alcohol plus glycerol or propylene glycol), or as lotions, creams and ointments (e.g. oil-in-water or water-in-oil emulsions). In addition, topical sunscreens preparations may be included in cosmetic preparations along with cosmetic agents such as pigments, perfumes, and the like.
Although many agents have been suggested as possibly providing systemic photoprotection after oral administration, evidence of their effectiveness remains largely anecdotal or inferential (see M. A. Pathak and T. B. Fitzpatrick (1994), supra). Even the mechanisms by which many of these agents may work is speculative, ranging from optical filtration and epidermal thickening to the inhibition of membrane-lipid peroxidation and protection of DNA from photodamage.
Polypodium is a genus of plants typical of the fern family, Polypodiaceae. In 1967, Horvath et al. reported that an extract or infusion of one species of fern, Polypodium leucotomos, traditionally used by the natives of northern Honduras as a treatment for malignant tumors, had been shown both in vitro and in vivo to have antitumoral effects (A. Horvath, et al., Nature 214:1256-1258 (1967)). Since then, extracts from a variety of fern plants, some referred to as Polypodium extracts and some referred to as calagualine, have been found to have a number of dermatological, immunomodulatory and behavioral effects.
Extracts of Polypodium leucotomos have been found effective in the treatment of psoriasis, atopic dermatitis and other skin disorders (see, e.g., H. Corrales Padilla, et al., Int. J. Dermatol. 13(5):276-282 (1974); D. Jimenez, et al., Allergol. et Immunopathol. 15(4):185-189 (1987)). In these settings, the extract was found to cause decreases in hyperkeratosis, parakeratosis, epidermal mitosis, epidermal thickening, epidermal prolongations, and the severity and extent of epidermal lesions.
Processes for producing polar extracts of the ferns Dryopteris crassirhizoma, polypodium vulgare, Linn, Polypodium leucotomos, Phlebodium decumanum, J. Smith, Polypodium decumanum, Cyathea taiwaniana, or rhizomes of Polypodium aureum, Linn., and Polypodium triseriales were disclosed in GB Patent 2,024,622A to Ramon, et al. (filed May 24, 1979). This patent also claimed medicaments prepared from such extracts and suggested their oral use in the treatment of psoriasis and parapsoriasis.
Similarly, processes for producing polar extracts from a variety of ferns of the family Polypodiaceae were disclosed in GB Patent 2,075,834A to Ramon et al. (filed Mar. 26, 1981). This patent suggested the oral use of such extracts in the treatment of osteolocomotive diseases (e.g., arthritis).
U.S. Pat. No. 4,206,222 to Valetas (issued Jun. 3, 1980) also discloses a method of producing extracts from a variety of ferns in the Polypodiaceae family. In addition, Valetas claims an active agent of a particular chemical structure, a C.sub.8 delta-lactone, isolated from these ferns. The active agent is disclosed to be useful in the treatment of collagen diseases (e.g. arthritis).
Extracts of Polypodium leucotomos also have been found to increase the number of T8 lymphocytes, to decrease the T4/T8 ratio in blood, to prolong the survival of skin allografts in mice, to inhibit the proliferative response of mouse spleen cells, and to inhibit the proliferative response of T lymphocytes to mitogens (see, e.g., J. Vargas, et al., Ann. Immunol. (Inst. Pasteur) 134(C):393-400 (1983); D. Jimenez, et al., Allergol. et Immunopathol. 15(4):185-189 (1987); M. Tuominen, et al., Phytother. Res. 5:234-236 (1991); D. Fernandez, et al., Book of Abstracts: First World Cong. Medicinal and Aromatic Plants for Human Welfare, Maastricht, Netherlands, Poster 84 (1992); J. Rayward, et al., Second Int. Cong. on Biol. Response Modifiers, San Diego, USA (1993)).
X. A. Alvafez, et al. tested the effects of a Polypodium extract on the behavior and brain cytokines of rats. Their data indicated that the extract induces hypokinesia at moderate-high doses, with no effect on psychomotor habituation, in an open-field psychomotor activity test; improves learning in a passive avoidance behavior test; decreases levels of the cytokines IL-1.beta. and IL-2 in frontoparietal cortices; decreases IL-1.beta. in the hippocampus; and increases TNF-.alpha. in the cortex (X. A. Alvarez, et al., Annals of Psychiatry 3:329-341 (1992)).
In another study, extracts of Polypodium decumanum ("Calaguala") were shown to inhibit the release of the proteolytic enzyme elastase in human neutrophils induced by platelet activating factor (PAF) and to inhibit the biosynthesis of PAF (M. Tuominen, et al., Planta Med. 58:306-310 (1992)). Because PAF may be involved in the pathogenesis of psoriasis, the authors of this study speculated that the anti-PAF activity of the extract may contribute to its clinical efficacy in the treatment of psoriasis.
Prior to the present invention, however, the photoprotective and antioxidant properties of topically applied and systemically administered Polypodium extract for normal skin were unknown. Thus too, prior to the present invention, methods of providing photoprotection and antioxidant protection by topical application or systemic administration of Polypodium extracts were unknown.